摘要
目的探讨以跨膜丝氨酸蛋白酶2(TMPRSS2)为受体的单体化合物治疗新型冠状病毒肺炎(COVID-19)的作用机制。方法借助BindingDB数据库检索作用于TMPRSS2受体的单体化合物。通过UniProt、GeneCards等数据库查询单体化合物作用靶点对应的基因名,进而运用Cytoscape 3.2.1构建化合物-靶点(基因)网络,通过WebGestalt数据库进行GO功能注释和Pathway通路分析,预测其作用机制。运用SWISS-MODEL进行TMPRSS2蛋白质三级结构预测,利用Auto Dock软件进行化合物与TMPRSS2受体的分子对接。结果通过BindingDB数据库发现3个作用于TMPRSS2的单体化合物:(2S)-1-[((2R)-2-(苄基磺酰基氨基)-5-(二氨基亚甲基氨基)戊酰基]-N-[(4-氨基甲酰基苯基)甲基]吡咯烷-2-羧酰胺(CID-46899577,分子式C26H36N8O4S)、4-[[[((5R)-5-(苄磺酰基氨基)-8-(二氨基甲基亚氨基)氨基-4-氧代辛烷-3-基]氨基]甲基]苯羧酰亚胺(CID-56677007,分子式C24H35N7O3S)、4-[[[((4S,6R)-6-(苄基磺酰基氨基)-9-(二氨基亚甲基氨基)-5-氧肟酮-4-基]氨基]甲基]苯羧酰亚胺(CID-56663319,分子式C25H37N7O3S);单体化合物-靶点网络中靶点58个,GO功能富集分析得到GO条目380个(P<0.05),其中生物过程(BP)条目310个,细胞组成(CC)条目14个,分子功能(MF)条目56个。KEGG通路富集筛选得到26条信号通路,涉及干扰素-γ信号传导途径、转化生长因子-β(TGF-β)信号通路、白介素信号通路等。分子对接结果显示,TMPRSS2与C26H36N8O4S、C24H35N7O3S及甲磺酸卡莫司他都能自发结合,且2种化合物与甲磺酸卡莫司他结合能相近。结论单体化合物C26H36N8O4S、C24H35N7O3S与TMPRSS2能自发结合,作用于F2、PLG、PLAU、PLAT、HSP90AA1、XIAP、AKT1、AKT2、AKT3等靶点调节多条信号通路,有可能对COVID-19有治疗作用。
Objective To explore the mechanism of monomeric treatment of corona virus disease 2019(COVID-19)by using transmembrane serine protease 2(TMPRSS2)as a receptor.Methods The monomer compounds acting on the TMPRSS2 receptor were searched by the BindingDB database.Use UniProt,GeneCards and other databases to query the gene name corresponding to the target of the monomer compound,and then use Cytoscape 3.2.1 to build a compound-target(gene)network.Use the WebGestalt database to perform GO function annotation and Pathway analysis to predict its mechanism.The third-order structure of TMPRSS2 protein was predicted by SWISS-MODEL,and the molecular docking between the compound and TMPRSS2 receptor was carried out by auto dock software.Results Three monomer compounds acting on TMPRSS2 were found through the BindingDB database:(2S)-1-[(2R)-2-(Benzylsulfonylamino)-5-Guanidino-Pentanoyl]-N-[(4-Carbamimidoylphenyl)methyl]pyrrolidine-2-Carboxamide(CID-46899577,Molecular formula:C26H36N8O4S),4-[[[(5R)-5-(Benzylsulfonylamino)-8-(diaminomethylideneamino)-4-oxooctan-3-yl]amino]methyl]benzenecarboximidamide(CID-56677007,Molecular formula:C24H35N7O3S),4-[[[(4 S,6 R)-6-(Benzylsulfonylamino)-9-(diaminomethylideneamino)-5-oxononan-4-yl]amino]methyl]benzenecarboximidamide(CID-56663319,Molecular formula:C25H37N7O3S).There were 58 targets in the monomer compound-target network,and 380 GO entries were obtained by GO functional enrichment analysis(P<0.05),including 310 biological process(BP)entries,14 cell composition(CC)entries,and molecules.There are 56 function(MF)entries.The KEGG pathway was enriched and screened to obtain 26 signaling pathways,which involved the interferon-γsignaling pathway,the TGF-beta signaling pathway,and the interleukin signaling pathway.The molecular docking results show that TMPRSS2 can spontaneously bind to the three compounds carmoselta mesylate C26H36N8O4S,and C24H35N7O3S.Conclusion Monomeric compounds C26H36N8O4S and C24H35N7O3S combined with TMPRSS2 act on targets such as F2,PLG,PLAU,PLAT,HSP90 AA1,XIAP,AKT1,
作者
徐昕怡
曹学帅
龙茜
刘乐平
唐吉伟
顾晖
XU Xinyi;CAO Xueshuai;LONG Xi;LIU Leping;TANG Jiwei;GU Hui(Department of Anesthesiology,Hunan Brain Hospital,Changsha 410006,China;Pharmacology Laboratory of Hunan University of traditional Chinese medicine,Changsha 410208,China;Department of blood transfusion,Xiangya Third Hospital,Central South University,Changsha 410000,China)
出处
《药物评价研究》
CAS
2020年第5期813-821,共9页
Drug Evaluation Research
基金
湖南省卫计委科研计划课题(B20180102、B20180714)。
